The long range objective of this Program Project is to develop and exploit new experimental approaches to elucidate the cellular and molecular mechanisms by which epidermal growth factor (EGF) regulates cell proliferation. The program contains research projects led by experienced investigators who propose to jointly utilize new technologies and systems for which preliminary data have been developed. All the projects are centered on the EGF receptor and ask how signals are received by this molecule and transmitted into biological responses. Project 1 will use molecular biological techniques to clone and characterize phosphorylation substrates of the EGF receptor. This project will employ similar methodologies to identify DNA sequences that are positively or negatively controlled by EGF. Project 2 will study, with biochemical and cell biological experiments, the mechanism by which EGF:receptor complexes communicate with the inositol phosphate pathway. The regulatory effects that the products of this pathway may have on cell growth control will also be investigated. Project 3 will develop and characterize biological information concerning growth regulation of an EGF-dependent epithelial cell line. This cell line will be utilized by several of the projects in different ways. Project 4 will study regulatory interactions between the platelet-derived growth factor and the EGF receptor. Project 5 will develop data on the mechanism by which growth factors affect the activity of DNA topoisomerases. Project 6 will employ electron microscopy to determine the physical distribution and interactions among key proteins in the EGF pathway. Project 7 will employ a biophysical methodology, electron paramagnetic resonance, to define details of EGF-receptor interactions that are not otherwise obtainable. These research projects will be supported by two core units. One core will provide preparative and analytical services, while the second core will provide centralized administrative support. The Program Project mechanism provides a unifying vehicle to maximize the concentration of specialized resources, both technical and intellectual, of the investigators for the benefit of individual research efforts and the long range goals. Personal collaborations among the investigators and a technically broad, but biologically focused and integrated system of experimental approaches will be uniquely available through the Program Project.